Fluorinated organic molecules are increasingly used in life science industries. The presence of a fluorine substituent can have positive effects on the biological properties of compounds. The substitution of a hydrogen atom with a fluorine atom in biologically active molecules often imparts improvements in bioavailability and/or metabolic stability. However, despite the importance of the incorporation of fluorine into organic molecules, there are relatively few selective and mild synthetic methods for C—F bond formation, particularly on process scale. Thus, synthetic techniques for fluorinating compounds are a significant area of interest.
One method for the industrial preparation of aryl and heteroaryl fluorides is nucleophilic aromatic fluorination (SNAr) or halex fluorination (Adams, D. J.; et al., Chem. Soc. Rev. 1999; 28:225; Langlois, B.; et al., In Industrial Chemistry Library; Jean-Roger, D.; Serge, R., Eds.; Elsevier: 1996; pp 244-292). This involves the reaction of an electron-deficient (hetero)aryl chloride or nitroarene with a nucleophilic fluoride source to generate the corresponding aryl fluoride (Id.; Kuduk, S. D.; et al., Org. Lett. 2005; 7:577). Anhydrous alkali metal fluorides (MF) are most commonly employed as the fluoride source. However, these salts are poorly soluble in organic solvents; as a result, high temperatures and long reaction times are necessary to obtain high yields of the fluorinated products. The forcing conditions can limit the functional group tolerance of these reactions and result in the formation of undesired side products (Id.).
Tetrabutylammonium fluoride (TBAF) has been used as a highly nucleophilic fluoride—ion source to fluorinate a variety of substrates. This reagent is prepared by treating tetrabutylammonium cyanide with hexafluorobenzene in a solvent and under anhydrous conditions. The resultant TBAF (i.e., TBAFanh or TBAF*) can then be used to fluorinate certain substrates. See DiMagno, et al., J. Am. Chem. Soc. 2005, 127, 2050-2051; DiMagno et al. Angew. Chem. Int. Ed. 2006, 45, 2720-2725; Allen, L.; et al., Org. Process. Res. Dev. 2014, 18(8):1045-1055; Allen, L.; et al., J. Org. Chem. 2014, 79(12):5827-5833. Similarly, the combination of acid fluorides and N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluoride reagents that participate in room temperature SNAr fluorination (Ryan, S. J.; et al., Org. Lett. 2015; 17:1866; Tang, P.; et al., J. Am. Chem. Soc. 2011; 133:11482; Fujimoto, T.; et al., Org. Process Res. Dev. 2014; 18:1041; Fujimoto, T.; et al. Org. Lett. 2015; 17:544).
While these methods have been successful in certain systems, they have limitations, such as poor selectivity and reactivity for certain substrates. These methods also require the use of expensive stoichiometric reagents (C6F6, NHCs) that preclude implementation on an industrial scale. What is needed are new methods for fluorinating compounds, especially a wide variety of fluorinated compounds, and the methods and compounds disclosed herein address these and other needs.